Older Recipient Age Research Articles

Donor hepatitis C seropositivity: clinical correlates and effect on early graft and patient survival in adult cadaveric kidney transplantation.

The impact of hepatitis C virus-positive donor kidneys on patient survival has not been analyzed in a national study. This study analyzed 20,111 adult (age, > or =16 yr) recipients having solitary cadaveric kidney transplants from adult donors with valid donor hepatitis C serologies from July 1, 1994, to June 30, 1998, in an historical cohort study (the 2000 United States Kidney Data System) of patient survival. Analysis was by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. Of 484 kidneys positive for hepatitis C virus serology, 165 (34%) were given to recipients with confirmed negative hepatitis C serologies. Unadjusted 3-yr patient survival was 93% in all recipients of donor hepatitis C-negative kidneys versus 85% in all recipients of donor hepatitis C-positive kidneys (P = 0.01). Among hepatitis C-positive recipients, those who received hepatitis C-positive kidneys had worse survival than recipients of hepatitis C-negative kidneys. Among elderly hepatitis C-negative recipients, those who received hepatitis C-positive kidneys also had worse survival; in fact, all recipients of donor hepatitis C-positive kidneys had increased risk of mortality (P = 0.028). There were no significant interactions between donor hepatitis C positivity and either recipient hepatitis C positivity or older recipient age. The use of hepatitis C-positive kidneys in recipients who were hepatitis C-negative was fairly common and contrary to some current recommendations. Recipients of donor hepatitis C-positive kidneys were at independently increased risk of mortality, with no evidence that any subgroups were less affected.

Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program

AbstractBetween April 1988 and July 1998, 510 patients with myelodysplastic syndromes (MDS) underwent unrelated donor bone marrow transplantation (BMT) facilitated by the National Marrow Donor Program. Median age was 38 years (range, <1-62 years). Several conditioning regimens and graft-versus-host disease (GVHD) prophylaxis methods were used, and T-cell depletion was used in 121 patients. Donors were serologically matched for HLA-A, -B, and -DRB1 antigens for 74% of patients. Of 437 patients evaluable for engraftment, 24 (5% cumulative incidence, with 95% confidence interval [CI] of 3%-7%) failed to engraft, and an additional 33 (8% cumulative incidence; 95% CI, 6%-10%) had late graft failure. Grades II to IV GVHD developed in 47% of patients (95% CI, 43%-49%), and limited and extensive chronic GVHD developed at 2 years in 27% (95% CI, 24%-30%). The incidence of relapse at 2 years was 14% (95% CI, 11%-17%). Greater relapse was independently associated with advanced MDS subtype and no acute GVHD. The estimated probability of disease-free survival (DFS) at 2 years was 29% (95% CI, 25%-33%). Improved DFS was independently associated with less advanced MDS subtype, higher cell dose, recipient cytomegalovirus (CMV) seronegativity, shorter interval from diagnosis to transplantation, and transplantation in recent years. Common causes of death were treatment-related complications accounting for 82% of fatalities. The 2-year cumulative incidence of treatment-related mortality (TRM) was 54% (95% CI, 53%-61%). Sixty-nine percent of TRM occurred within the first 100 days, and 93% occurred within the first year of transplantation. Higher TRM was independently associated with older recipient and donor age, HLA mismatch, and recipient CMV seropositivity. This study demonstrates that unrelated donor BMT cures a significant proportion of patients with MDS. TRM is the major problem limiting the success of unrelated donor BMT in MDS. The observations made in this study should facilitate the design of prospective trials aimed at improving the results of unrelated donor stem cell transplantation for MDS.

Chronic graft-versus-host disease: clinical manifestation and therapy.

Chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in long-term survivors of allogeneic stem cell transplantation. The immunopathogenesis of chronic GVHD is, in part, TH-2 mediated, resulting in a syndrome of immunodeficiency and an autoimmune disorder. The most important risk factor for chronic GVHD is prior history of acute GVHD and strategies that prevent acute GVHD also decrease the risk of chronic GVHD. Other important risk factors are the use of a non-T cell-depleted graft, and older age of donor and recipient. Whether recipients of peripheral blood stem cells are at increased risk of chronic GVHD remains unsettled. There are no known pharmacologic agents which can specifically prevent development of chronic GVHD. Agents which have efficacy in the treatment of autoimmune disorders have been utilized as therapy for established chronic GVHD and are associated with response rates of 20% to 80%. Most responses are confined to skin, soft tissue, oral mucosa and occasionally liver. Bronchiolitis obliterans responds infrequently to therapy and is associated with a dismal prognosis. Newer, promising therapeutic strategies under investigation include thalidomide, photopheresis therapy, anti-tumor necrosis factor and B cell depletion with anti-CD20 monoclonal antibody.

Risk factors for corneal graft failure and rejection in penetrating keratoplasty.

To evaluate risk factors for graft failure and allograft rejection after penetrating keratoplasty (PK). We retrospectively studied clinical results of PKs in terms of graft survival and rejection-free graft survival rates. PKs were done on 271 eyes between 1987 and 1997. Clinical results were analyzed by Kaplan-Meier's life table method and the log-rank test. Relative risks and adjusted survival probabilities for each value of the factor were compared with the risk for a specified reference value. The overall rates of graft survival and rejection-free graft survival in 10 years after PK were 79.3% and 77.9%, respectively. Higher relative risk of graft failure was associated with corneal vascularization (relative risk for within one quadrant = 1.67, two quadrants = 2.37, three or more quadrants = 3.39), regraft (relative risk for one failed previously graft = 2.08, two or more failed previously graft = 2.65), aphakia (relative risk = 2.17) or pseudophakia (relative risk = 3.02), presence of anterior synechia (relative risk = 2.91), presence of posterior synechia (relative risk = 2.56), long (more than 85 minutes) operation time (relative risk = 2.20), and older (more than 50 years) recipient age (relative risk = 2.38). Higher relative risk of rejection was associated with corneal vascularization (relative risk for within one quadrant = 2.35, two quadrants = 2.03, three or more quadrants = 2.63), long (more than 85 minutes) operation time (relative risk = 1.47), and younger (less than 60 years) donor age (relative risk = 2.10). There was no association between graft failure or allograft rejection and graft size or suture technique, respectively. The risk factors for graft failure after PK were corneal vascularization, regraft, aphakia or pseudophakia, presence of anterior synechia, presence of posterior synechia, long operation time, and older recipient age. The risk factors after PK for allograft rejection were corneal vascularization, long operation time, and younger donor age.

Risk factors for chronic graft-versus-host disease after allogeneic stem cell transplantation in children.

We analyzed the incidence and risk factors for chronic graft-versus-host disease (GVHD) in 265 children undergoing allogeneic stem cell transplantation (SCT) who survived longer than 3 months post SCT. Patients transplanted from HLA-mismatched related donors and matched unrelated donors were included. Fifty-five patients developed chronic GVHD between 1 and 25 months after SCT, and the 5-year cumulative incidence of chronic GVHD was 22%. By multivariate analysis, acute GVHD (P = 0.004), malignant disease (P = 0.004), recipient age (> or =10 years) (P = 0.01) and a female donor to male recipient (P = 0.035) were significant risk factors for chronic GVHD. When acute GVHD was excluded from the multivariate analysis, malignant disease (P = 0.002) and older recipient age (P = 0.007) were identified. The incidence of chronic GVHD in this childhood study was lower than that observed in adults, and recipient age was an important factor in childhood SCT. The high incidence associated with malignant disease may be affected by changes in GVHD prophylaxis in order to ensure graft-versus-tumor effects.

Death after rejection with severe hemodynamic compromise in pediatric heart transplant recipients: a multi-institutional study

Background: Rejection with severe hemodynamic compromise results in high mortality in adult transplant patients. This study determines the incidence, outcome and risk factors for rejection with severe hemodynamic compromise in a multi-institutional study of pediatric heart transplant recipients. Methods Data from 847 patients transplanted between 1/1/93 and 12/31/98 at 18 centers in the Pediatric Heart Transplant Study were analyzed. Rejection with severe hemodynamic compromise was defined as a clinical event occurring beyond 1 week postoperatively, which led to augmentation of immunosuppression and use of inotropic therapy. Actuarial freedom from such rejection and death after rejection were determined and risk factors sought. Results Among 1,033 rejection episodes in 532 patients, 113 (11%) episodes were associated with severe hemodynamic compromise in 95 patients. The highest risk for severe rejection was in the first year. Risk factors were older recipient age ( p >.05) and non-white race ( p >.001). Survival after an episode was poor (60%), and biopsy score did not affect outcome. Deaths were due to rejection ( n = 14), other cardiac causes ( n = 17), infection ( n = 5), lymphoma ( n = 2), pulmonary causes ( n = 2), and thrombosis ( n = 1). Conclusions Rejection with severe hemodynamic compromise occurs in 11% of pediatric patients, irrespective of age, sex or biopsy score, and mortality is high. Non-white race and older recipient age are independent risk factors for rejection with severe hemodynamic compromise. Aggressive treatment and close surveillance should be crucial components of protocols aimed at reducing the high mortality.

Older recipient age is associated with reduced alloreactivity and graft rejection after cardiac transplantation

Older recipients are considered to be high-risk for transplantation because of the presence of comorbid conditions. However, since the overall integrity of the immune system progressively decreases with age, we hypothesized that a similar age-related decline occurs in immunological alloreactivity, and that this might paradoxically improve post-transplant outcomes in older patients. Among 337 adult recipients of a primary cardiac allograft between 1992-1999 (mean age 51+13 years), cumulative annual rejection (ISHLT grade 3A) frequency was significantly lower in those >60 years (n=97) than in those <60 years (n=227), 0.21 vs 1.03, p=0.02). No difference in rejection were detected among patients <60 stratified by deciles. Moreover, those >60 had longer duration to a first rejection, with only 43% rejecting within 5 years compared with 64% of those <60, p=0.005. In addition, recipients >60 demonstrated reduced anti-donor alloreactivity as defined by IL-2 receptor positive T cell outgrowth from biopsy sites and IgG anti-HLA antibodies. By 12 months post-transplant, only 37% of those >60 had one or more episode of IL2 receptor-positive T cell outgrowth compared with 72% of those <60 (p=0.01). This was accompanied by reduced production of IgG anti-HLA antibodies (p=0.23). Since the period of maximal alloreactivity and risk for rejection is the first three months post-transplant, we compared three month survival in these groups. Recipients >60 years had significantly higher 3-month survival compared with those <60 (96% vs 90%, p=0.02). Of 19 deaths in the group <60, 16 (84%) were due to either acute rejection or infections secondary to immunosuppression. In contrast, 5-year survival was similar between the two groups (76% vs 69%, p=0.54). We conclude that cardiac transplant recipients over 60 years demonstrate reduced anti-donor alloreactivity, resulting in decreased risk for acute rejection and significantly increased early survival. Since long-term survival is comparable in this group to that in younger patients, cardiac transplantation in the older recipient should be strongly encouraged.

Cytomegalovirus and the aging population.

Human cytomegalovirus (HCMV) has the largest genome of any virus known to infect man. The virus has evolved many strategies to manipulate the host immune systems and so can remain latent and evade important immune responses. The human host mounts a substantial immune response against the virus, with up to 1% of the virus-specific CD8+ T cells being directed against specific epitopes. Acquisition of HCMV occurs progressively from an early age, and in developed countries the overall seroprevalence is approximately 60%. In contrast, specific communities such as gay men, lower socioeconomic groups and people residing in developing countries have seroprevalence rates that can exceed 90%. It is a widely held belief that successful control of viral infections decreases with increasing age because of a reduction in the capacity of the immune system. Studies in aging populations have shown a specific expansion of the CD8+, CD28- and CD57+ subset of cells in patients who are HCMV-seropositive. Prior infection with HCMV has also been associated with a significantly increased number of CD4+ and CD8+ lymphocytes, as well as cells expressing CD56 and HLA-DR. Thus, HCMV infection can cause substantial perturbations in T cell subsets and these effects persist in the aging population. In the context of solid organ transplantation, older age of both recipients and donors may serve to increase the frequency of donor-positive recipient-positive (D+R+) transplants, which have only a moderate risk of HCMV disease. In the context of HIV infection, age has been a dominant risk factor for progression to AIDS and death. At present, it does not appear that this can be explained by lack of immune control of HCMV in the aging population, although studies have identified prior HCMV infection as a risk factor for AIDS and death independent of age. We await further investigations to determine whether the immune control of HCMV in the elderly patient is as effective as in the younger adult, and whether this is linked to pathological consequences.

Initial endothelial cell density and chronic endothelial cell loss rate in corneal transplants with late endothelial failure

Objective To determine when corneal transplants develop the decreased endothelial cell density that predisposes to late endothelial failure (LEF). Design Noted cohort study within a prospective case series. Participants The authors compared 21 grafts that developed LEF with the remaining transplants (controls) in a longitudinal cohort study of 500 consecutive penetrating keratoplasties by 1 surgeon. Eyes regrafted during the study, fellow eyes of bilateral cases, and patients who did not want their data used for research purposes were excluded, leaving 389 grafts in 389 patients for analysis. Intervention Penetrating keratoplasty. Main outcome measures Endothelial cell density before surgery and at 2 months and 1, 3, 5, and 10 years after surgery. Results Grafts with LEF had lower median endothelial cell densities than other grafts, both before surgery (2710 cells/mm 2 vs. 2991 cells/mm 2; P = 0.02) and 2 months after surgery (1895 cells/mm 2 vs. 2501 cells/mm 2; P < 0.001), a difference that was maintained through 5 postoperative years. Despite having lower preoperative cell densities, the grafts with LEF had larger median endothelial cell losses 2 months after keratoplasty (31% vs. 16%, P = 0.002). The endothelial cell loss subsequent to the 2-month examination, however, was not increased in the grafts with LEF. Risk factors for developing LEF included a low endothelial cell density before surgery ( P = 0.007) and 2 months after surgery ( P = 0.002), aphakia or pseudophakia ( P = 0.04), older recipient age ( P = 0.002) and older donor age ( P = 0.03), and occurrence of an endothelial rejection episode ( P = 0.03). Conclusions Corneal grafts with LEF, the major cause of graft failure after 5 postoperative years, fail from low initial endothelial cell density rather than an increased rate of chronic postoperative cell loss. Improved techniques of corneal preservation should decrease the rate of LEF. In addition to low preoperative and 2-month postoperative endothelial cell density, a higher risk of LEF is also seen in patients with aphakia or pseudophakia, older recipient age, older donor age, and occurrence of an endothelial rejection episode.

Cyclosporin Maintenance Monotherapy After Renal Transplantation

The use of cyclosporin monotherapy as maintenance immunosuppression in primary cadaveric renal transplant recipients is not popular except in a few European centres. Corticosteroid withdrawal is becoming more popular, and is usually attempted with the newer immunosuppressants which have a more corticosteroid-sparing effect than cyclosporin. The adverse effects and morbidity associated with maintenance regimens consisting of 2 or 3 immunosuppressive drugs are well known, but the potential benefits of cyclosporin monotherapy must be balanced against an increased risk of graft loss by rejection. We selected patients for a trial of corticosteroid withdrawal and subsequent cyclosporin monotherapy. These patients received an individually designed immunosuppressive regimen with careful control of cyclosporin trough concentrations. The cyclosporin formulations used were its original oil-based solution or gelatin capsule (Sandimmun, Sandimmune )until mid-1996 and then the microemulsion formulation (Neoral). Corticosteroid withdrawal was attempted in 89% of patients with a graft functioning at 3 months after transplantation and was effective in 88% of them. At a mean follow-up time of 98 +/- 23 months, 69% of grafts were functioning and 92% of patients were alive. 50% of patients with a functioning graft were receiving long term cyclosporin monotherapy. Mild rejection episodes occurred in 6% of patients receiving cyclosporin monotherapy per year of treatment, and chronic rejection caused graft loss in 1.4% of patients per year of treatment. Comparison of successful and unsuccessful outcomes allows us to define favourable predictive factors. For corticosteroid withdrawal these are: older recipient age, lower creatininaemia at months 6 and 8 and higher trough cyclosporin concentrations at month 6. For cyclosporin monotherapy these are: later timing of azathioprine withdrawal, recipient age >25 years, donor age <or=40 years, creatininaemia <or=125 micromol/L at initiation of monotherapy and no rejection episode before initiation of monotherapy. We have observed a low incidence of nonmelanoma skin cancers and of squamous-cell carcinoma in our series. This is perhaps the result of the azathioprine-sparing effects of the regimen (7 azathioprine-free years per patient with successful cyclosporin monotherapy, and 4 azathioprine-free years per patient with unsuccessful monotherapy). This important point will need further studies but is encouraging. Maintenance cyclosporin monotherapy is feasible and probably useful in selected primary graft recipients without deleterious effects on overall results in terms of graft and patient survival. Careful patient selection using the predictive factors we have defined should make cyclosporin monotherapy more effective, allowing the present 57% success rate at 5 years post-transplantation to be increased by 15 or 20%.

Surgical complications requiring early relaparotomy after pancreas transplantation: a multivariate risk factor and economic impact analysis of the cyclosporine era.

To study significant surgical complications requiring early (< or = 3 months posttransplant) relaparotomy (relap) after pancreas transplants, and to develop clinically relevant surgical and peritransplant decision-making guidelines for preventing and managing such complications. Pancreas grafts are still associated with the highest surgical complication rate of all routinely transplanted solid organs. However, the impact of surgical complications on morbidity, hospital costs, and graft and patient survival rates has not been analyzed in detail to date. We retrospectively studied surgical complications requiring relap in 441 consecutive cadaver, bladder-drained pancreas transplants (54% simultaneous pancreas and kidney [SPK]; 22% pancreas after kidney [PAK]; 24% pancreas transplant alone [PTA]; 37% retransplant). Outcome and hospital charges were analyzed separately for recipients with versus without reoperation. The overall relap rate was 32% (SPK, 36%; PAK, 25%; PTA, 16%; p = 0.04). The most common causes were intraabdominal infection and graft pancreatitis (38%), pancreas graft thrombosis (27%), and anastomotic leak (15%). Perioperative relap mortality was 9%; transplant pancreatectomy was necessary in 57% of all recipients with one or more relaps. The pancreas graft was lost in 80% of recipients with versus 41% without relap (p < 0.0001). Patient survival rates were significantly lower (p < 0.05) for recipients with versus without relap. By multivariate analysis, significant risk factors for graft loss included older donor age (SPK, PAK), retransplant (PAK), relap for infection (SPK, PAK), and relap for leak or bleeding (PAK). For death, risk factors included older recipient age (SPK, PAK),retransplant (SPK, PAK), relap for thrombosis (PAK), relap for infection or leak (SPK), and relap for bleeding (PTA). Posttransplant surgical complications requiring relap were frequent, resulted in a high rate of pancreas (SPK, PAK, PTA) and kidney (SPK, PAK) graft loss, and had a major economic impact (p = 0.0001). Complications were associated with substantial perioperative mortality and decreased patient survival rates. The focus must therefore shift from graft salvage to preservation of the recipient's life once a pancreas graft-related complication requiring relap occurs. Thus, the threshold for pancreatectomy should be low. In this context, acceptance of older donors and recipients must be reconsidered.

Unrelated donor bone marrow transplantation for hematological malignancies-current status.

We have explored the efficacy and toxicity of hematopoietic stem cell transplantation from unrelated donors for hematologic malignancies and other disorders. While most marrow donors have been identified through the National Marrow Donor Program in cooperation with many international registries, the recent development of unrelated donor umbilical cord blood (UCB) banks has allowed us to also evaluate this stem cell source. Analysis of the first 211 URD BMT performed at the University of Minnesota shows an overall survival of 33%, with older recipient age and transplant from a donor with a major HLA-A or B mismatch independently associated with poorer survival. Analysis of engraftment of URD marrow shows increasing risk of delayed or incomplete engraftment with increasing HLA disparity between URD and recipient. GVHD is increased in recipients of URD marrow compared with recipients of related donor marrow. Malignant relapse, however, is less frequent in URD marrow recipients, perhaps due to an increased graft-versus-leukemia effect. Formal assessment shows quality of life in long term URD BMT survivors (beyond 2 years) is excellent, and not different from that seen in sibling marrow recipients. Data from patients receiving unrelated donor UCB transplantation at the University of Minnesota indicate that UCB is an acceptable alternate source of stem cells, at least for young recipients, and may be associated with a reduced incidence of GVHD. Ongoing studies at the University of Minnesota include examination of the applicability of unrelated UCB transplantation to adult recipients, and of the degree of HLA-incompatibility which can be tolerated in UCB transplantation. Studies to identify the optimal GVHD prophylaxis for URD BMT, and to examine the role of class II matching in transplant outcome are in progress.

969-94 A Prospective, Randomized Steroid-free Maintenance Protocol in Heart Transplant Recipients

Immunosuppressive therapy for orthotopic heart transplant (OHT) recipients should be tailored in an effort to minimize steroid-induced morbidity. Accordingly, to assess the feasibility of and to identify specific predictors of successful steroid-withdrawal following OHT. we prospectively randomized 34 OHT recipients to cyclosporine/prednisone/azathioprine (CPA; n = 19) vs. cyclosporine/azathioprine (CA; n = 15) maintenance therapy. Mean followup was 1.6 ± 0.1 yr. No perioperative Iymphocytolytic induction therapy was used. End-point comparisons between CPA and CA groups included the percent of patients steroid-free at 1 yr, total rejection episodes (≥ IHSLT IIIA). number of major infections. blood pressure. hypercholesterolemia and survival. Total ischemic time. pre-transplant diagnosis. recipient/donor age and gender, and mean PRA levels were similar between the two groups. In the CA group. the mean post-OHT time to steroid-free was 228 d (range 167–356 d) with 9/15 (60%) maintained steroid-free at one-yr. Patients were considered steroid-free failures if they experienced ≥ 2 episodes of moderate-severe rejection requiring augmentation of immunotherapy. No differences in the number or duration of rejection episodes. major infections, systolic/diastolic BP or total cholesterol were observed between the two groups. The univariate predictors of successful steroid-withdrawal included: 1) male donor(p &lt; 0.02); 2) older recipient age (58 ± 2 vs. 48 ± 3 yrs; p = 0.02); and 3) older donor age (34 ± 6 vs. 21 ± 2 yrs; p &lt; 0.06). No difference in 1 yr survival was observed between the CPA vs CA groups. as determined by Kaplan-Meier analysis. Steroid-withdrawal following OHT is not associated with increased morbidity and/or mortality. We believe that this data is of importance for the future rational design of “individualized” immunosuppression following OHT.

Cardiac transplantation: The Stanford experience in the cyclosporine era

We analyzed our experience with 496 patients who underwent primary cardiac transplantation since the introduction of cyclosporine immunosuppression (Dec. 16, 1980, to Jan. 7, 1993). There were 388 male and 108 female patients. Mean recipient age was 40 ± 16 years (range 0.1 to 70 years, median 44 years). Recipient diagnoses included coronary disease in 188, idiopathic cardiomyopathy in 196, viral cardiomyopathy in 35, and congenital heart disease in 28 patients. Donor age was 25 ± 10 years (range 1 to 53 years, median 24 years). Graft ischemic time was 148 ± 57 minutes (range 38 to 495 minutes, median 149 minutes). Operative mortality (hospital death) rate was 7.9% ± 1.3% (70% confidence intervals). Multivariate logistic regression analysis revealed that (higher) pulmonary vascular resistance and gender (female) were the only independent predictors of hospital death ( p < 0.05). Actuarial survival estimates for all patients at 1, 5, and 10 years are 82% ± 1.7% (83% ± 1.8% adult, 77% ± 5.2% pediatric), 61% ± 2.5% (65% ± 2.5% adult, 64% ± 6.6% pediatric), and 41% ± 3.7% (40% ± 4% adult, 54% ± 8.6% pediatric), respectively. For 232 patients treated with triple-drug immunosuppression and induction with OKT3 since 1987, survival estimates at 1 and 5 years are 82% ± 2.6% and 67% ± 3.7%, respectively. Causes of death for the entire group were rejection in 29 (14% of deaths), infection in 69 (34%), graft coronary disease in 36 (18%), nonspecific graft failure in 6 (3%), malignancy in 19 (10%), stroke in 6 (3%), pulmonary hypertension in 6 (3%), and other causes in 30 (15%) patients. Actuarial freedom from rejection at 3 months, 1 year, and 5 years was 21% ± 1.9%, 14% ± 1.7%, and 7.2% ± 1.5%, respectively (±1 standard error of the mean). Estimates of freedom from rejection-related death at 1, 5, and 10 years were 96% ± 1%, 93% ± 1.4%, and 93% ± 1.4%, respectively. Actuarial freedom from any infection at 3 months and at 1 and 5 years was 40% ± 2.3%, 27% ± 2.1%, and 15% ± 2.0% and from infection-related death, 95% ± 1.0%, 93% ± 1.2%, and 85% ± 1.9%, respectively. Actuarial freedom from (angiographic or autopsy proved) graft coronary artery disease at 1, 5, and 10 years was 95% ± 1.2%, 73% ± 2.7%, and 65% ± 3.6% and from coronary disease–related death or retransplantation 98% ± 0.7%, 84% ± 2.2%, and 66% ± 4.3%, respectively. Multivariate (Cox model) proportional hazard regression analysis revealed that (older) recipient age and race (nonwhite) were independent predictors of late (as opposed to hospital) death ( p < 0.05). Immunosuppressive protocol was an independent predictor ( p < 0.05) of freedom from rejection (but not from late death or from rejection-related death). These data demonstrate satisfactory long-term results of cardiac transplantation for treatment of patients with end-stage heart disease. (J T HORAC C ARDIOVASC S URG 1994;108:240-52)

BRONCHIOLITIS ASSOCIATED WITH BONE MARROW TRANSPLANTATION

New onset airflow obstruction after BMT is a relatively common complication and may be seen in as many as 11% of long-term survivors of allogeneic BMT with chronic GVHD. Bronchiolitis and, occasionally, obliterative bronchiolitis is seen in the majority of cases in which histopathology is available. The primary risk factors recognized are the presence of clinical chronic GVHD, administration of methotrexate as an immunosuppressive, and older recipient age. Improved control of chronic GVHD with effective agents such as cyclosporine likely will decrease the incidence of this airway disorder. The causes probably are multifactorial and donor cytotoxic T-lymphocyte interaction with host cells is a likely contributor in many cases. The clinical course is variable, but the process usually is fatal in cases with rapidly progressive or severe obstruction. Interventions are directed at immune suppression and at diagnosing and treating infections that frequently occur in association with the airflow obstruction.

RISK FACTORS FOR ACUTE GRAFT-VERSUS-HOST DISEASE IN HISTOCOMPATIBLE DONOR BONE MARROW TRANSPLANTATION

We have analyzed factors associated with acute graft-versus-host disease following allogeneic bone marrow transplantation in 469 patients with histocompatible sibling donors between 1979 and 1987. Overall, 46 +/- 5% (95% confidence interval) developed clinical grade II-IV acute GVHD following transplantation. In univariate analysis, patient or donor age greater than or equal to 18 years was significantly associated with increased GVHD risks (greater than or equal to 18, 63 +/- 6% grade II-IV GVHD vs. less than 18, 27 +/- 6%, P less than .0001), without incremental risk in older adults. Univariate analysis showed that donor:recipient sex match and female:female transplants were associated with less-frequent GVHD. More frequent GVHD was associated with chronic myelogenous leukemia, cytomegalovirus seropositivity, and prior donor alloimmunity (pregnancy or transfusion). Additionally, the allele HLA-A26 was associated with increased risk of GVHD (72%, P = .005) while HLA-DR3 was associated with less GVHD (31%, P = .03). Stepwise multivariate analysis confirmed the increased GVHD risks associated with older recipient age, HLA-A26 and donor:recipient gender (not female:female) and the protective effect of HLA-DR3. Similar results were found using the different analytic technique of recursive partition analysis, which identified within the adult population the lowest GVHD risk in female recipients with nonalloimmunized female donors (20%), while other gender combinations had 68% acute GVHD, regardless of donor alloimmunity. In children (less than 18 years), lower GVHD risk accompanied donor:recipient sex-matched (18%) versus mismatched (33%) BMT. Clinical trials undertaken to lessen the hazards of GVHD must be designed with appropriate attention to these reproducibly identified clinical variables associated with different GVHD risks.

Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome

We have analyzed the long term outcome of 197 patients who were treated for grade II to IV acute graft-versus-host disease (GVHD) following histocompatible allogeneic bone marrow transplantation (BMT). Of 469 recipients of sibling donor allografts performed at our center between January, 1979 and October, 1987, 197 patients (42%) developed greater than or equal to grade II acute GVHD at a median of 38 days (range 9 to 98 days) post-BMT. After treatment with corticosteroids (n = 160) or other immunosuppressive therapies (n = 37), 72 patients (41% +/- 8%; 95% confidence interval [CI]) achieved complete and continuing resolution of acute GVHD after a median of 21 days of therapy. Sixty- one patients required additional immunosuppressive therapy with high dose methylprednisolone, antithymocyte globulin (ATG)/steroids, or other therapies because of refractory or progressive symptoms of acute GVHD. Seven of these 61 patients eventually obtained complete and continuing remission after 13 to 57 days (median 50) of secondary treatment. The overall rate of chronic GVHD was 70% +/- 16%; 95% CI following grade II to IV acute GVHD. Twenty-five of the 197 patients never developed chronic GVHD, resulting in a Kaplan-Meier projection of 30% +/- 8% (95% CI) cure of moderate/severe acute GVHD. Analysis of clinical features associated with complete response (CR) to acute GVHD therapy identified more favorable responses to therapy in patients without either liver or skin involvement, patients with acute lymphoblastic leukemia, and donor/recipient pairs other than male patients with female donors. Older recipient age was not associated with more resistance to GVHD treatment. CR to GVHD treatment was associated with significantly better 5-year survival: 51% +/- 14% versus 32% +/- 11% for patients with therapy resistant acute GVHD (P = .004). GVHD was a major contributing cause of death in 49 of the 90 patients who died and was often complicated by infection or interstitial pneumonitis. Control of acute GVHD through immunosuppressive therapy did not affect the risk of leukemic relapse after transplantation.

Treatment of Moderate/Severe Acute Graft-Versus-Host Disease After Allogeneic Bone Marrow Transplantation: An Analysis of Clinical Risk Features and Outcome

We have analyzed the long term outcome of 197 patients who were treated for grade II to IV acute graft-versus-host disease (GVHD) following histocompatible allogeneic bone marrow transplantation (BMT). Of 469 recipients of sibling donor allografts performed at our center between January, 1979 and October, 1987, 197 patients (42%) developed greater than or equal to grade II acute GVHD at a median of 38 days (range 9 to 98 days) post-BMT. After treatment with corticosteroids (n = 160) or other immunosuppressive therapies (n = 37), 72 patients (41% +/- 8%; 95% confidence interval [CI]) achieved complete and continuing resolution of acute GVHD after a median of 21 days of therapy. Sixty-one patients required additional immunosuppressive therapy with high dose methylprednisolone, antithymocyte globulin (ATG)/steroids, or other therapies because of refractory or progressive symptoms of acute GVHD. Seven of these 61 patients eventually obtained complete and continuing remission after 13 to 57 days (median 50) of secondary treatment. The overall rate of chronic GVHD was 70% +/- 16%; 95% CI following grade II to IV acute GVHD. Twenty-five of the 197 patients never developed chronic GVHD, resulting in a Kaplan-Meier projection of 30% +/- 8% (95% CI) cure of moderate/severe acute GVHD. Analysis of clinical features associated with complete response (CR) to acute GVHD therapy identified more favorable responses to therapy in patients without either liver or skin involvement, patients with acute lymphoblastic leukemia, and donor/recipient pairs other than male patients with female donors. Older recipient age was not associated with more resistance to GVHD treatment. CR to GVHD treatment was associated with significantly better 5-year survival: 51% +/- 14% versus 32% +/- 11% for patients with therapy resistant acute GVHD (P = .004). GVHD was a major contributing cause of death in 49 of the 90 patients who died and was often complicated by infection or interstitial pneumonitis. Control of acute GVHD through immunosuppressive therapy did not affect the risk of leukemic relapse after transplantation.

Favourable outcome of patients older than 40 years of age after transplantation with marrow grafts depleted of lymphocytes by counterflow centrifugation

Nineteen patients with a median age of 43 years (range 40-48) were transplanted for acute myelogenous leukaemia (AML), refractory anaemia with excess of blasts in transformation (RAEBt), acute lymphoblastic leukaemia (ALL) in first complete remission, multiple myeloma, and chronic myelogenous leukaemia (CML) in chronic or accelerated phase. Their outcome was compared with that of 35 patients with a median age of 34 years (range 30-39), and a group of patients with age younger than 30 years (median 24; range 16-29) transplanted for the same indications. Donors were human leucocyte antigen (HLA)-identical, mixed lymphocyte culture (MLC) negative siblings. All marrow grafts were depleted of lymphocytes by counterflow centrifugation. The estimated event-free survival at 3 years after allogeneic bone marrow transplantation was 60.7% for patients with age greater than 39 years, 57.8% for patients with age less than 30, and 43.0% for the intermediate age group (P greater than 0.3). The estimated transplant-related mortality showed no tendency to increase with older age of recipients. The incidence of acute GVHD greater than grade 1 was 15.7% in patients with age greater than 39 years, 9.5% in patients younger than 30 years, and 23% in the intermediate age group. The incidence of chronic GVHD was higher in the older patients (39% compared to 24% in patients younger than 30 years, 19% in the intermediate age group). Chronic GVHD resolved completely in five out of seven patients aged 40 years or more. Reduction of the incidence of acute graft-versus-host disease by physical lymphocyte depletion allows allogeneic bone marrow transplantation for patients aged 40-50 years without increase of transplant-related mortality resulting in similar event-free survival in patients older than 40 years compared to those younger than 40 years.

ABO compatibility and acute graft-versus-host disease following allogeneic bone marrow transplantation.

If ABO antigens/antibodies play any role in the pathogenesis of acute graft-versus-host disease (GVHD), one would expect the highest incidence of GVHD in recipients of minor ABO-mismatched grafts, followed by ABO-matched grafts, and the lowest incidence in major ABO-mismatched transplants. To test this hypothesis 174 patients receiving an HLA-identical allogeneic bone marrow transplant (BMT) for aplastic anemia (n = 32) or leukemia (n = 142) were analyzed for factors associated with acute GVHD. Variables analyzed included diagnosis, sex, age, blood group of donor and recipient, ABO compatibility, Rhesus compatibility, sex compatibility, number of bone marrow cells given at BMT, year of transplant, day of engraftment, and GVHD prophylaxis. We first carried out an exploratory contingency table analysis: minor ABO incompatibility was associated with a significantly higher risk of severe acute GVHD when compared with ABO-matched and major-ABO mismatched pairs (P = 0.003): 14/9, 57/67, and 5/22 patients developed, respectively, 0-I/II-IV acute GVHD in ABO major-mismatched, matched, and minor-mismatched pairs. Donors of group 0, (P = 0.06), older recipient's age (P = 0.08), fast engraftment (P = 0.03), and older donor's age (0.08) were also associated with a higher risk of GVHD. Recipient's ABO group, diagnosis, year of transplant, Rhesus group of donor or recipient, Rhesus compatibility, sex of donor or recipient, sex compatibility, and type of GVHD prophylaxis were not predictive of GVHD. A Cox multifactorial proportional hazards analysis confirmed that ABO matching was the single most significant factor associated with GVHD (P = 0.006). The cumulative incidence of GVHD grade II+ was 39%, 54%, and 82% for ABO major-mismatched, matched, and minor-mismatched pairs (P = 0.01). This study suggests that ABO antigens may play a role in the development of acute GVHD.